We report the results from one site of a two-site, double-blind, placebo-controlled comparison study of gepirone extended release (ER) and imipramine in the management of major depression. In the study, 123 subjects with DSM-III-R major depression were randomized to 8 weeks of treatment with gepirone ER (10-60 mg/day), imipramine (50-300 mg/day), or placebo. According to last observation carried forward (LOCF) analyses of 120 intent-to-treat subjects, both gepirone ER and imipramine were superior to placebo at Weeks 6 and 8 on the Hamilton Rating Scale for Depression 17- and 28-item (HAM-D-17 and HAM-D-28) instruments, the Clinical Global Impressions (CGI) Severity of illness scale, and the total Bech Six-Item Core Depression Cluster score. Gepirone ER was better tolerated than imipramine when judged by dropout rates for adverse events.